Development of an improved blood-stage malaria vaccine targeting the essential RH5-CyRPA-RIPR invasion complex.

Reticulocyte-binding protein homologue 5 (RH5), a leading blood-stage Plasmodium falciparum malaria vaccine target, interacts with cysteine-rich protective antigen (CyRPA) and RH5-interacting protein (RIPR) to form an essential heterotrimeric "RCR-complex". We investigate whether RCR-complex vaccination can improve upon RH5 alone. Using monoclonal antibodies (mAbs) we show that parasite growth-inhibitory epitopes on each antigen are surface-exposed on the RCR-complex and that mAb pairs targeting different antigens can function additively or synergistically.

Tackling barriers to COVID-19 vaccine uptake in London: a mixed-methods evaluation.

Background: In response to the COVID-19 pandemic, the first vaccine was administered in December 2020 in England. However, vaccination uptake has historically been lower in London than in other English regions.

Methods: Mixed-methods: This comprised an analysis of cumulative percentage uptake across London between 8 December 2020 and 6 June 2021 by vaccine priority cohorts and ethnicity.

Heterotypic interactions drive antibody synergy against a malaria vaccine candidate.

Understanding mechanisms of antibody synergy is important for vaccine design and antibody cocktail development. Examples of synergy between antibodies are well-documented, but the mechanisms underlying these relationships often remain poorly understood. The leading blood-stage malaria vaccine candidate, CyRPA, is essential for invasion of Plasmodium falciparum into human erythrocytes.

Key findings from the UKCCMP cohort of 877 patients with haematological malignancy and COVID-19: disease control as an important factor relative to recent chemotherapy or anti-CD20 therapy.

Patients with haematological malignancies have a high risk of severe infection and death from SARS-CoV-2. In this prospective observational study, we investigated the impact of cancer type, disease activity, and treatment in 877 unvaccinated UK patients with SARS-CoV-2 infection and active haematological cancer. The primary end-point was all-cause mortality.

The patient safety collaborative programme: opportunities for physician engagement.

Driving improvements in patient safety has been a core goal of the Academic Health Science Networks (AHSNs) in England since their inception in 2013. The National Patient Safety Collaborative Programme, nested within the 15 geographically located AHSNs, was established in 2014 in response to the Berwick review. In 2019, the new NHS national patient safety strategy was published, which placed the AHSNs as a key vehicle for delivering its ambitions.

Functional Comparison of Blood-Stage Malaria Vaccine Candidate Antigens.

The malaria genome encodes over 5,000 proteins and many of these have also been proposed to be potential vaccine candidates, although few of these have been tested clinically. RH5 is one of the leading blood-stage malaria vaccine antigens and Phase I/II clinical trials of vaccines containing this antigen are currently underway. Its likely mechanism of action is to elicit antibodies that can neutralize merozoites by blocking their invasion of red blood cells (RBC).

MSR1 repeats modulate gene expression and affect risk of breast and prostate cancer.

Background: MSR1 repeats are a 36-38 bp minisatellite element that have recently been implicated in the regulation of gene expression, through copy number variation (CNV).

Patients And Methods: Bioinformatic and experimental methods were used to assess the distribution of MSR1 across the genome, evaluate the regulatory potential of such elements and explore the role of MSR1 elements in cancer, particularly non-familial breast cancer and prostate cancer.

Results: MSR1s are predominately located at chromosome 19 and are functionally enriched in regulatory regions of the genome, particularly regions implicated in short-range regulatory activities (H3K27ac, H3K4me1 and H3K4me3).

Overcoming Challenges In Codifying And Replicating Complex Health Care Interventions.

The complex nature of many health care interventions poses challenges for successful replication. This article presents insights on tackling these challenges primarily drawn from recent research and programs in the UK. These insights include the need to codify complex interventions in ways that reflect their social, context-sensitive, and dynamic nature; to capture learning as the intervention is implemented in new contexts; and to design programs in ways that respect adopters' role in the spread process.

Functional Characterization and Comparison of Proteins as Targets of Transmission-blocking Antibodies.

malaria continues to evade control efforts, utilizing highly specialized sexual-stages to transmit infection between the human host and mosquito vector. In a vaccination model, antibodies directed to sexual-stage antigens, when ingested in the mosquito blood meal, can inhibit parasite growth in the midgut and consequently arrest transmission. Despite multiple datasets for the sexual-stage transcriptome and proteome, there have been no rational screens to identify candidate antigens for transmission-blocking vaccine (TBV) development.

Asymmetrical transfer effects of cognitive bias modification: Modifying attention to threat influences interpretation of emotional ambiguity, but not vice versa.

Background And Objectives: It is well established that attention bias and interpretation bias each have a key role in the development and continuation of anxiety. How the biases may interact with one another in anxiety is, however, poorly understood. Using cognitive bias modification techniques, the present study examined whether training a more positive interpretation bias or attention bias resulted in transfer of effects to the untrained cognitive domain.

Production of full-length soluble Plasmodium falciparum RH5 protein vaccine using a Drosophila melanogaster Schneider 2 stable cell line system.

The Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) has recently emerged as a leading candidate antigen against the blood-stage human malaria parasite. However it has proved challenging to identify a heterologous expression platform that can produce a soluble protein-based vaccine in a manner compliant with current Good Manufacturing Practice (cGMP). Here we report the production of full-length PfRH5 protein using a cGMP-compliant platform called ExpreS(2), based on a Drosophila melanogaster Schneider 2 (S2) stable cell line system.

Progress with viral vectored malaria vaccines: A multi-stage approach involving "unnatural immunity".

Viral vectors used in heterologous prime-boost regimens are one of very few vaccination approaches that have yielded significant protection against controlled human malaria infections. Recently, protection induced by chimpanzee adenovirus priming and modified vaccinia Ankara boosting using the ME-TRAP insert has been correlated with the induction of potent CD8(+) T cell responses. This regimen has progressed to field studies where efficacy against infection has now been reported.

A method for identifying associations between seizures and possible trigger events in adults with intellectual disability.

Objectives: Precipitants of seizures are often reported by patients and carers, but the accuracy of these claims remains unknown. Focusing on epilepsy in people with intellectual disability (ID), the aims of this work were to (1) identify a set of methods for assessing the validity of reported seizure triggers in individual patients; and (2) undertake an initial assessment of the ease of implementation and acceptability of the method by applying it to a series of cases.

Methods: Data collection materials (developed with carer involvement) consisted primarily of carer diaries of seizure and trigger occurrences.

Prime-boost vaccination with chimpanzee adenovirus and modified vaccinia Ankara encoding TRAP provides partial protection against Plasmodium falciparum infection in Kenyan adults.

Protective immunity to the liver stage of the malaria parasite can be conferred by vaccine-induced T cells, but no subunit vaccination approach based on cellular immunity has shown efficacy in field studies. We randomly allocated 121 healthy adult male volunteers in Kilifi, Kenya, to vaccination with the recombinant viral vectors chimpanzee adenovirus 63 (ChAd63) and modified vaccinia Ankara (MVA), both encoding the malaria peptide sequence ME-TRAP (the multiple epitope string and thrombospondin-related adhesion protein), or to vaccination with rabies vaccine as a control. We gave antimalarials to clear parasitemia and conducted PCR (polymerase chain reaction) analysis on blood samples three times a week to identify infection with the malaria parasite Plasmodium falciparum.

A PfRH5-based vaccine is efficacious against heterologous strain blood-stage Plasmodium falciparum infection in aotus monkeys.

Antigenic diversity has posed a critical barrier to vaccine development against the pathogenic blood-stage infection of the human malaria parasite Plasmodium falciparum. To date, only strain-specific protection has been reported by trials of such vaccines in nonhuman primates. We recently showed that P.

Developing and testing a framework to measure and monitor safety in healthcare.

The NHS excels at measuring incidences of past harm - whether it is falls or hospital-acquired infections - but research undertaken by Charles Vincent, Jane Carthey and Susan Burnett for the Health Foundation suggests past harm is only one element of what is needed to understand how safe care is. The researchers developed a framework to incorporate other necessary elements, such as anticipating and preparing for risks before they lead to harm to patients. In 2013, the Health Foundation road-tested this framework with staff in three NHS organisations and held a two-day summit with leaders from across the healthcare system to get feedback on its potential.

Evaluation of the efficacy of ChAd63-MVA vectored vaccines expressing circumsporozoite protein and ME-TRAP against controlled human malaria infection in malaria-naive individuals.

Background: Circumsporozoite protein (CS) is the antigenic target for RTS,S, the most advanced malaria vaccine to date. Heterologous prime-boost with the viral vectors simian adenovirus 63 (ChAd63)-modified vaccinia virus Ankara (MVA) is the most potent inducer of T-cells in humans, demonstrating significant efficacy when expressing the preerythrocytic antigen insert multiple epitope-thrombospondin-related adhesion protein (ME-TRAP). We hypothesized that ChAd63-MVA containing CS may result in a significant clinical protective efficacy.

Why do seizures occur when they do? Situations perceived to be associated with increased or decreased seizure likelihood in people with epilepsy and intellectual disability.

Seizure precipitants are commonly reported in the general population of people with epilepsy. However, there has been little research in this area in people with epilepsy and intellectual disability (ID). We conducted a survey of the situations associated with increased or decreased seizure likelihood in this population.

Combining viral vectored and protein-in-adjuvant vaccines against the blood-stage malaria antigen AMA1: report on a phase 1a clinical trial.

The development of effective vaccines against difficult disease targets will require the identification of new subunit vaccination strategies that can induce and maintain effective immune responses in humans. Here we report on a phase 1a clinical trial using the AMA1 antigen from the blood-stage Plasmodium falciparum malaria parasite delivered either as recombinant protein formulated with Alhydrogel adjuvant with and without CPG 7909, or using recombinant vectored vaccines--chimpanzee adenovirus ChAd63 and the orthopoxvirus MVA. A variety of promising "mixed-modality" regimens were tested.

Structure of malaria invasion protein RH5 with erythrocyte basigin and blocking antibodies.

Invasion of host erythrocytes is essential to the life cycle of Plasmodium parasites and development of the pathology of malaria. The stages of erythrocyte invasion, including initial contact, apical reorientation, junction formation, and active invagination, are directed by coordinated release of specialized apical organelles and their parasite protein contents. Among these proteins, and central to invasion by all species, are two parasite protein families, the reticulocyte-binding protein homologue (RH) and erythrocyte-binding like proteins, which mediate host-parasite interactions.

Domain Anomaly Detection in Machine Perception: A System Architecture and Taxonomy.

We address the problem of anomaly detection in machine perception. The concept of domain anomaly is introduced as distinct from the conventional notion of anomaly used in the literature. We propose a unified framework for anomaly detection which exposes the multifaceted nature of anomalies and suggest effective mechanisms for identifying and distinguishing each facet as instruments for domain anomaly detection.

Effects of standard and explicit cognitive bias modification and computer-administered cognitive-behaviour therapy on cognitive biases and social anxiety.

Background And Objectives: This study examines the effects of a single session of Cognitive Bias Modification to induce positive Interpretative bias (CBM-I) using standard or explicit instructions and an analogue of computer-administered CBT (c-CBT) program on modifying cognitive biases and social anxiety.

Methods: A sample of 76 volunteers with social anxiety attended a research site. At both pre- and post-test, participants completed two computer-administered tests of interpretative and attentional biases and a self-report measure of social anxiety.

Modifying social anxiety related to a real-life stressor using online Cognitive Bias Modification for interpretation.

Modifying threat related biases in attention and interpretation has been shown to successfully reduce global symptoms of anxiety in high anxious and clinically anxious samples (termed Cognitive Bias Modification, CBM). However, the possibility that CBM can be used as a way to prevent anxiety associated with an upcoming real-life stressful event in vulnerable populations has yet to be systematically examined. The present study aimed to assess whether a two-week course of online CBM for interpretations (CBM-I) could reduce social evaluative fear when starting university.